Table 1.

Molecular and clinical presentations of COG complex mutations.

Gene	Mutation	Effect on mutant subunit	Effect on COG complex	Clinical presentation	Refs
COG1	Homozygous 2659-2660insC (p.P888fsX900)	Truncated by 80aa at C-terminus due to premature stop codon Around 15% of mutant COG1 expressed and weakly localized to the Golgi	Depletion of all lobe A subunits and COG8	Feeding problems since birth, failure to thrive, hypotonia, psychomotor and growth retardation, short stature, microcephaly, liver and spleen enlargement, small hands and feet, straightened bitemporal space, antimongoloid eyelids, cardiac abnormalities included ventricular hypertrophy	[87]
	Homozygous c.1070 + 5G > A	Mutant COG1 truncated by 321aa due to loss of exon 6 and new stop codon in exon 7. Truncated COG1 not expressed. Low protein levels of WT COG1 present	Decreased COG8 protein levels	More severe than the previous COG1-CDG. Cerebrocostomandibular syndrome including mental retardation, cerebellar atrophy, renal and cardiac abnormalities, arthrogryposis, hearing loss and skeletal abnormalities.	[114]
COG2	Heterozygous mutations: •c.701dup (p.Y234*) •c.1900 T > G (p.W634G)	c.701dup mRNA is not expressed. c.1900 T > G mRNA expressed is low levels. COG2 protein is non-detected.	Decreased COG3, COG4 levels	Growth retardation, microcephaly, spastic quadriplegia, liver dysfunction, hypocupremia, hypoceruloplasminemia, cerebral atrophy and tonic seizures	[89]
COG4	c.2185C > T (p.R729W) 16q22 deletion	80% depletion of COG4 protein	Decreased COG1, COG2, COG3 COG5 levels	Mild psychomotor retardation, dysmorphia, epilepsia	[90]
	Heterozygous •c.697G > T (p.E233X) [de novo] •c.2318 T > G (p.L773R)	Degradation of c.697G > T mRNA 70% depletion of COG4	No significant effect on other COG subunits		[92]
	Heterozygous de novo •c.1546G > A or •c.1546G > C (p.G516R)	–	No effect on other subunits	Skeletal dysplasia caused by Saul-Wilson Syndrome, developmental delay and dysmorphic features	[91]
COG5	Homozygous c.1669-15 T > C	Intronic substitution caused skipping of exons 15 & 16. Truncated COG5 (by 58aa) not expressed. Low levels of WT COG5 expressed	–	Mild neurological phenotype including hypotonia, psychomotor retardation, delayed speech development and truncal ataxia	[93]
	Heterozygous •c.556_560delAGTAAinsCT (p.S186_K187delinsL) •c.1856 T > C (p.I619T) [c.95 T > G (p.M32R)]	Deletion predicted to be in frame Affected M is in a highly conserved region 75% depletion of COG5	About 90% depletion of COG5	Same as above with cirrhotic liver and hepatosplenomegaly	[94]
	Homozygous c.2518G > T (p.E840X)	75% depletion of COG5		Microcephaly, delayed speech, and motor development, moderate to severe mental retardation, hypotonia, mild dysmorphia, microcephaly, short stature and walking difficulty	[69]
	Heterozygous •c.189delG (p.C64Vfs*6) •c.2338_2340dupATT (p.I780dup)			Same as above with blindness and deafness
	Homozygous c.1780G > T (p.V594F)	Skipping of exon 16 75% depletion of COG5		Same as above with blindness and deafness.
	Heterozygous c.1209delG (p.M403IfsX3)	Depletion of WT COG5. Low levels of mutant COG5 also present.	–	Friedreich's-ataxia-like phenotype including cerebellar atrophy, mild to moderate intellectual disability, and scoliosis.	[95]
	Heterozygous •c.2324C > T (p.P775L) •c.330delT (p.V111Lfs*22)	P775 and V111 are highly conserved in mammals. Truncated p.V111Lfs*22 (by 690aa) non- functional	–	Most severe COG5-CDG phenotype including severe mental retardation, delayed speech and motor development, microcephaly, cerebral and cerebellar atrophy, hypotonia, recurrent seizures, liver involvement and small feet.	[96]
	Heterozygous •c.1290C > A (p.Y430X) •c.2077A > C (p.T693P)	T693 is highly conserved 80% depletion of WT COG5. Truncated COG5 present at very low levels	–	Neonatal jaundice, recurrent upper respiratory tract infections, hypohidrosis, hyperkeratosis, ulnar deviation and delayed psychomotor development.	[97]
	Heterozygous •c.2324C > T (p.P775L) •c.1508dup (p.G505Wfs*3)	–	–	Neurodevelopmental disorders, non-syndromic intellectual disability	[134]
COG6	Homozygous c. 1646G > T (p.G549V)	80% depletion of COG6	Decreased COG5, COG7 levels. Assembly of octameric COG unaffected	Fatal (2 siblings died within 2 months of birth.) Major neurologic involvement, intractable focal seizures, vomiting, intracranial bleedings causing loss of consciousness, cholestasis, vitamin K deficiency, brain oedema, necrotizing enterocolitis with disseminated intravascular coagulation.	[70,135]
		–	–	Fatal. Died at the age of 6 Chronic inflammatory bowel disease, gastrointestinal malabsorption, liver cirrhosis, mild psychomotor retardation, and microcephaly, recurrent infections due to immunodeficiency, failure to thrive.	[99]
	c.1167-24A > G (p.G390FfsX6)	Intronic mutation created a new splice site. Mutant COG6 not expressed 30% of WT COG6 protein present	–	Shaheen syndrome (mild intellectual disability, hypohidrosis, abnormal teeth, and acquired microcephaly, palmoplantar hyperkeratosis)	[100]
		–	–	Shaheen syndrome, strabismus, splenomegaly, hypotonia, HLH	[101]
	Homozygous c.511C > T (p.R171*)		–	Fatal. Died a few days after birth. Respiratory failure extreme hypotonia	[102]
	Homozygous c.1746 + 2 T > G	Splice site mutation	–	Fatal. (All patients died within 1 year) Developmental disability, chronic diarrhea with failure to thrive, splenomegaly, hypotonia and recurrent infections, bilateral sensorineural hearing loss, enlarged extra-axial CSF spaces and asymmetric lateral ventricles.
	Homozygous c.1238_1239insA (p.F414Lfs*4)	–	–	Fatal. Died at the age of 1 year. Psychomotor disability, failure to thrive, chronic diarrhea and hepatosplenomegaly, recurrent infections from immune dysfunction, liver failure
	Heterozygous •c.1646G > T (p.G549V) •c.785A > G (p.Y262C)	–	–	Microcephaly, splenomegaly, and delay in motor development, gastroenteritis, high fever, and convulsions, recurrent infections from immune dysfunction
	Heterozygous •c.511C > T (p.R171*) •c.1746 + 2 T > G.	–	–	2 siblings, one died at 15 months Diarrhea, fever at birth due to viral infection, hepatosplenomegaly, cirrhotic liver, psychomotor disability, hypotonia, scoliosis, microcephaly, dysmorphia, and growth retardation recurrent infections and hyperthermia
COG7	Homozygous IVS1 + 4 A → C aka c.169 + 4A > C	Intronic mutation in splice site 19 bp deletion due to altered splicing and premature stop codon Degradation of COG7 mRNA Less than 20% protein expressed	Decreased COG5 (95%), COG6 (70%), and COG8 (71%) Lobe A associated with the Golgi, not lobe B	Fatal. Cardiac failure and other complications within the first year of birth. Perinatal asphyxia, dysmorphia, skeletal deformities, hypotonia, hepatosplenomegaly, neonatal jaundice, recurrent epilepsies, infections	[[105], [106], [107]]
	Homozygous c.170-7A > G (p.56–57insAT)	Activation of upstream cryptic splice site inserted 6 bps between exon 1 and 2 About 70% protein expressed	COG6 and COG8 levels decreased by 20% COG5 decreased by 60%	Milder clinical phenotype including growth retardation, failure to thrive, feeding problems, hypotonia, recurrent hyperthermia and cerebral atrophy	[109]
COG8	Homozygous c.1611C > G (p.Y537X)	Loss of 76-C terminus amino acids due to a premature stop codon. 25% of truncated COG8 is expressed	Decreased COG1, COG2, COG3, COG6 and COG7 Golgi localization of COG subunits unaffected. Octameric COG assembly affected	Acute encephalopathy, loss of psychomotor abilities, mild dysmorphia, hypotonia, alternating esotropia, pseudo-ptosis, unregulated coagulation, mental retardation, cerebellar ataxia, PFAPA syndrome during infancy, oculomotor apraxia with dysinergia oculocephalica and pseudo-ptosis	[37]
	Heterozygous •IVS3 + 1G > A •TT 1687–1688	G > A in intron 3 alters splicing leads to protein truncation by 306aa at the C-terminal TT deletion in exon 5 creates a premature stop codon and truncates the protein by 76aa COG8 protein is undetected	Decreased COG1, COG5, COG6 and COG7 by 60–70% COG2, COG3 and COG4 associated with the Golgi	Severe growth retardation, Hypotonia, decreased reflexes, chronic axonal neuropathy, ventriculomegaly ex vacuo with atrophy, seizures, esotropia/amblyopia, keratosis pilaris, mild spasticity and contractures, and no bowel/bladder control.	[110]
	Heterozygous •c.171dupG (p.L58Afs*29) •c.1656dupC (p.A553Rfs*15)	–	–	Psychomotor retardation, hypotonia, failure to thrive, microcephaly, skeletal deformities, and mild psychomotor retardation.	[111]
	Homozygous c.1583-1G > A	G > A at intron-exon boundary of intron 4	–	Fatal. Died 2 days after birth with severe neurological defects. Antenatal conditions included increased nuchal translucency, arthrogryposis multiplex congenita, Dandy-Walker malformation and fetal growth restrictions.	[112]